C3手性合成子的合成及应用

2006 年第14卷合成化学Vol. 14 ,2006第6期,546~551Chinese Journal of Synthetic ChemistryNo. 6 ,546 ~551.综合评述.C3手性合成子的合成及应用彭焕庆'2 ,王立新' ,杜振军' ,蔡泽贵' ,王文'( 1.中国科学院成都有机化学研究所四川成都610041 ;2. 中国科学院研究生院北京100039 )摘要:简要介绍了两种重要的C3手性合成子一环 氧氯丙烷( ECH )和缩水甘油( GLD )的合成方法综述了ECH在药物合成以及GLD在部分有机合成中的应用。参考文献34篇。关键词:C3合成子;环氧氯丙烷;缩水甘油;合成;综述中图分类号:0621.3文献标识码:A .文章编号: 1005-1511( 2006 )06-0546-06Syntheses and Applications of Chiral C3 SynthonsPENG Huan-qing'2 ,WANG Li-xin' ,DU Zhen-jun',CAI Ze-gui'，WANG Wen'( 1. Chengdu Institute of Organic Chemistry , Chinese Academy of Sciences , Chengdu 610041 China ;2. Graduate University of Chinese Academy of Sciences , Beijing 100039 , China ))Abstract : Synthetic methods of two C3 chiral synthon[ epichlorohydrin( ECH ) and glycido( GLD )]was introduced. The applications of ECH in drug synthesis and GLD in some organic synthesis werereviewed.34 references were cited.Keywords : C3 synthons ; chiral epichlorohydrin ; glyeidol ; synthesis ; review近年来,C3手性合成子在医药农药、香料、法和醋酸丙烯酯法其工业年产量约92万吨。手液晶高分子材料等领域得到了广泛的应用其合性的ECH是1978年由Baldwin等'首次以D-甘成研究也越来越受到人们的重视。常见的C3手露醇为原料合成的收率仅为27%[( R )-ECH和性合成子为C3环氧化合物及其前体卤代丙醇( S- )ECH的e.e.值都大于99% )。 随后又有其它等。本文着重介绍了环氧氯丙烷( ECH ,Chart 1 )的制备手性ECH的方法陆续报道2-01。但是这在药物合成中的应用和缩水甘油( GLD , Chart 1 )些合成及拆分方法的收率都不高。直到1995年，在有机合成中的部分应用。Jacobsen等7]将用于不对称环氧化的Cr -Salen催0ClOH化剂用于ECH的拆分,得到48%的收率( 97%e.e. )。1997年Jacobsen 等81又用Co-Salen催化ECHGLDCPD剂实现了ECH的拆分使收率达到了40%( 98%Chart 1e.e. )。 1999年Jacobsen等9]又报道了高分子负1 ECH 的不对称合成载的Co-Salen催化剂用于ECH的拆分，也得到了ECH的工业生产方法主要为丙烯高温氯化很[中国煤化工% e.e. )。YHCNMHG*收稿日期:2006-02-16 ;修订日期: 2006-05-25作者简介:彭焕庆( 1981- )男汉族山东菏泽人在读硕士主要从事医药中间体及相关化合物的合成研究。通讯联系人:王立新研究员主要从事医药及医药中间体等相关功能化合物的合成、技术改进与创新及产业化研究。Tel.028 -85255208 , E-mail :wkxioc@ cioc. ac. cn第6期彭焕庆等:C3手性合成子的合成及应用一547一2GLD及CPD的不对称合成3 ECH在药物合成中的应用1942年,Fischer 等10以D-甘露醇为原料合成3.1用于芳 氧丙醇胺类药物的合成了光学纯的GLD其(R-)GLD和(S)-GLD的收率.芳氧丙醇胺类药物是在上世纪中期发现的β肾分别为94%( >82% e.e. ),52%( >87% e.e. )。上腺素拮抗剂。其β受体阻断作用比苯乙醇胺类后来Sharpless等" 1用不对称环氧化反应实现了强对β,受体具有较高的选择性151。从该类药物的GLD的不对称合成,收率虽只有65%,但其通式我们可以发现以ECH作为合成原料是条简捷( R- )GLD和( S- )GLD的对映选择性都高于91%，的合成路线Scheme 1 )如已知的作用最强的β受创造了可以商业化的不对称GLD的合成方法。体阻断剂噻吗洛尔16]特异性最高的β受体阻断剂1990年ACROS公司12]应用Ti与D或L酒石酸比索洛尔17]超短效β受体阻断剂艾司洛尔18]为二异丙酯的配合物,在枯烯和双氧水条件下首次适应高血压患者而开发的长效β受体阻断剂纳多洛实现了GLD的商业化生产。同时Ladner等12 ]通尔19 '等( Chart 2都是以上述方法合成的。，过酶水解拆分方法制得了手性的GLD。CPD是GLD的前体光学纯的CPD主要由ECH动力学3.2用于 L-肉碱的合成水解拆分法制备。近年来也有其他不对称合成方ECH还普遍用于L_肉碱的合成。1992 年,法报道如1999年Hollingsworth等13以( S )-3-羟Kasai等20]通过1与三甲胺水溶液同步加成消去基丁内酯为原料合成了( R )-CPD ,收率83%反应合成2。2与2-甲基-2-羟基丙氰反应后经水( >99.5% e.e. )。 2003年,Prati 等[14]以1 3-二解得3。1997 年, Kabat等211同样用4与格氏试氯丙酮为原料合成了( R )-CPD ,收率82%( 99%剂反应得到5。5经三甲胺的亲核取代、阴离子交换反应氧化反应得到6( Scheme 2 )。e.e. )。cArOH 0vNH2ROAr一Ar0丫NHR.OHScheme 1比索洛尔噻鸣洛尔是HO*艾司洛尔纳多洛尔Chart 2.只30% NMes、只1. Me2C(CN)OH;2. concHCI HO2C-. cl中国煤化工HO"~HTHCNMHG_Mge1. NMe3(aq); 2. AmbedileOIRA 410(0H)- O2C~CICuBrHOrH3. O3, AcOH, then H2O24“H5Scheme 2一548一合成化学Vol. 14 ,20063.3在阿伐他汀 合成中的应用氢氧化钠催化下经亲核加成并同步关环制得对叔阿伐他汀钙是由美国沃那兰博特公司开发的丁基苯缩水甘油醚。对叔J基苯缩水甘油醚再经HMG-CoA还原酶抑制剂类血脂调节药。现为全过进一步反应制得TX-1898等系列化合物。球销售额最大的药物之一。在阿伐他汀的合成中,4-氯-3~羟基丁酸酯是重要的中间体,可由3.5在 杂环化合物中的应用ECH同氰基开环或与-氧化碳以羰基钴为催化在杂环化合物的合成中,1 2-二活性中心或剂在醇溶液中开环得到Scheme 3 )22，该中间体1 3-二活性中心化合物的应用非常广泛。ECH中主要用于阿伐他汀侧链的合成( Scheme4 )21。有3个活性中心在杂环化合物的合成上人们充OH O分应用了这种性质。文献26-281以ECH为原料合0CO. MeOH, Co(CO)、cICI、成了一些杂环化合物Scheme5 )。‘H0H+ cl美,CN3.6 同1 3-二噻烷阴离子的作用1997年,Smith 等(29 ]报道了二噻烷阴离子同Scheme 3两种不同的端基环氧化合物一锅法合成手性1 ,3.4在放射致敏剂合 成中的应用5-二醇类化合物的方法。2003 年,Smith 等301又1997年,Hitoshi Hori等241用ECH为原料合报道了二噻烷阴离子同-系列的光学纯的端基环成了TX-1845 ,TX-1846( Chart 3 )等高效的缺氧细氧化合物的反应。当他们以ECH为底物时发现胞放射致敏剂和血管发生抑制剂。2004 年他们25]其可以在低摩尔比的情况下较充分的同二噻烷阴又报道了TX-1898等系列放射致敏剂( Chart 3 )。离子反应得到构型翻转的端基环氧化合物类化合该类药物的合成方法是由ECH和对叔丁基苯酚在物( Scheme 6 )。QHNaCN。cnutto+ cn儿CO,BuPFPNH2Ph、HQr-CNPhHNOC'PrOH-CO2H +--- R-E0.一←R-B-CO2Bu'Scheme 4RO,B,XR0-_xNO2TX-1845: R= tert butyi:-1897: Ru ptert. butyiphenyl, X=C1TX-1899: R= p.tert. butylphemyl, X=C1TX-1846: R= P-lant. butylpbenyl:-1898: Ro p-tert butyiphenyl, X=BrTX-1900: R= p-tert- butylphenyl, X=BrChart 3- NHNH21. ECH, EtOH: 2.170 C-200 c,O,291中国煤化工-CHOECH. NH4OH, EtDHCNMH G76%. ro人aN≈C= =0ECH, Bu2Snl2 Ph3P、C83%Scheme 5第6期彭焕庆等:C3手性合成子的合成及应用-549一合成方法来实现了二半乳糖缩水甘油酯的合成1.1Bul,Eb0:2.E COBnTBSQ( Scheme 7 )。- TBSBnO、3.9 CI4.2二羟 基丙酮磷酸酯( DHAP )前体的合成<-1.BuL.ELO:2.它oen。TBSODHAP在有机合成中是一个重要的亲核试3.9a剂主要用于和醛加成合成邻二醇化合物。2004.年,Meyer等3以GLD为原料经过磷酸酯化得Scheme 6到缩水甘油磷酸酯18。18 在分子筛和三氟化硼4 GLD 的应用的催化下同苄醇发生加成反应后经氧化得到DHAP前体19( Scheme 8 )。4.1半乳糖甘 油酯的合成半乳糖甘油酯类化合物是一类在植物的细胞4.3氨基-1 4-二缩水_D~戊糖醇和氨基-1 ,5-二膜和细菌的细胞壁内分布广泛的一类化合物。 之缩水-D-己糖醇类化合物的合成前只是在哺乳动物的睾丸和神经系统细胞中发现光学纯的氨基缩水糖醇是-类具有单糖结构了单半乳糖甘油酯及磺化的单半乳糖甘油酯。的化合物。经常用作氨基酸前体和很多其他有机2001年,Pahlsson等31]在结肠癌HT29线细胞中物的前体在天然化合物的全合成等领域得到了广发现了单半乳糖缩水甘油酯及二半乳糖缩水甘油泛应用。2003 年,Aragone 等34以GLD为原料合酯。2002 年,Lindberg等32]则以GLD为原料合成了一系列氨基-1 4-二缩水-D-_戊糖醇和氨基-1 5-成了单半乳糖缩水甘油酯及二聚半乳糖缩水甘油二缩水-D-己糖醇类化合物。他们用( R )-GLD制得酯。他们首先以7与GLD经缩合制得8。8经过20。20经消去开环、醚化、环化分别制得五元环化保护基团的转变、碱性开环等反应步骤最后得到合物23和六元环化合物27。23和27分别经环氧单半乳糖缩水甘油酯11。他们也应用了同样的化、叠氮加成、水解制得24和28Scheme9)。0Bz OBz0R ORQR2 ,OR?QOR'R?oLBz0J-SEt.RO-0C1gH31OR?OBzOR8 R=Bz10 Rl=H ; R2=Bn7十9 R=Bn+11 R'=C1gHyCO; R2_HOH 0BzQBn OBnOBn,OBn一QBz0LBrnO120Bz0BnOBn .ROLRO-OCgHssBnO--SEt厂14 R=Bz.18 R=Bn, R'=Cj5HsCO13OBn15 R=BnL -17 R-H, R'=CjsH,COScheme 7020人0H--+0- -P- -OBr中国煤化工.MHCNMHG|1819Scheme 8一550一合成化学Vol. 14 ,2006TrO-RO-QH_，RO)-→OH212223Ro_e20NH22:6228Scheme 9参考文献[ 11] Klunde J M , KoS Y , Sharpless K B. 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